Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

Weston, Cathryn; Lü, Jing; Li, Naichang; Barkan, Kerry; Richards, Gareth O.; Roberts, David; Skerry, Timothy M.; Poyner, David R.; Pardamwar, Meenakshi; Reynolds, Christopher A.; Dowell, Simon J.; Willars, Gary B.; Ladds, Graham

doi:10.1074/jbc.m114.624601

Cited by 64 publications

(112 citation statements)

References 51 publications

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“…We have previously used the methods developed by Figuero et al 37 to quantify ligand bias for receptors expressed in yeast. 19,20 Here we report the adaptation of the equimolar method of comparison 37 to quantify a ligands selectivity for a given receptor (see Experimental Section for more details). Since NECA is a full agonist for all three ARs expressed in yeast, it can be used as a reference ligand.…”

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confidence: 99%

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

et al. 2016

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Running Title: Investigating adenosine receptor selectivity of N 6 -modified agonists.Keywords: GPCRs; adenosine receptor; selectivity; G proteins; yeast. 2 AbstractA series of N 6 -bicyclic and N 6 -(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N 6 -adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes these compounds might have therapeutic potential.3

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confidence: 99%

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

et al. 2016

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“…GPCRs are also highly druggable therapeutic targets (1). Receptor activity-modifying proteins (RAMPs) change ligand specificity, trafficking, and posttranslational modification of several GPCRs (2)(3)(4). For example, RAMPs facilitates the transport of calcitonin receptor-like receptor (CALCRL) to the plasma membrane (3), and the ligand specificity of the calcitonin receptor is altered in the presence of RAMPs (5,6).…”

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confidence: 99%

GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

Barbash

Lorenzen

Persson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Receptor activity-modifying proteins (RAMPs) are widely expressed in human tissues and, in some cases, have been shown to affect surface expression or ligand specificity of G-protein-coupled receptors (GPCRs). However, whether RAMP−GPCR interactions are widespread, and the nature of their functional consequences, remains largely unknown. In humans, there are three RAMPs and over 800 expressed GPCRs, making direct experimental approaches challenging. We analyzed relevant genomic data from all currently available sequenced organisms. We discovered that RAMPs and GPCRs tend to have orthologs in the same species and have correlated phylogenetic trees to the same extent, or higher than other interacting protein pairs that play key roles in cellular signaling. In addition, the resulting RAMP−GPCR interaction map suggests that RAMP1 and RAMP3 interact with the same set of GPCRs, which implies functional redundancy. We next analyzed human transcriptomes and found expression correlation for GPCRs and RAMPs. Our results suggest global coevolution of GPCRs and RAMPS and support the hypothesis that GPCRs interact globally with RAMPs in cellular signaling pathways.coevolution | G-protein-coupled receptor | phylogenetic analysis | receptor activity-modifying protein | signal transduction

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“…An initial study showed that the parathyroid type 1 and 2 receptors, the vasoactive intestinal polypeptide/pituitary adenylate cyclase activating peptide (VPAC) 1 and the glucagon receptor could promote RAMP trafficking to the plasma membrane. Further studies have extended this and characterized the effects of the interactions, using expression in both mammalian cells and the yeast Saccharomyces cerevisiae [24,32,33,36,37]. Several features have emerged from these studies.…”

Section: Ramp Interaction Partners and Their Functionsmentioning

confidence: 95%

“…To crystallize the ECD complexes a fusion protein strategy was adopted, with a single polypeptide chain made up of maltose binding protein (MBP), the ECD of either RAMP1 or RAMP2, a glycine-serine-alanine linker, the ECD of CLR and finally a hexahistidine tag [8] (Table 1). High resolution crystals were obtained with a modified CGRP fragment CGRP [27][28][29][30][31][32][33][34][35][36][37] [Asp 31 , Pro 34 , Phe 35 ] [14] or AM . The C-terminal residue of the peptide (Phe 37 for the CGRP derivative, Tyr 52 for AM) was the main contact with the RAMP.…”

Section: Structure Of Ramps and Ramp-receptor Complexesmentioning

confidence: 99%

Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

Hay

Walker

Gingell

et al. 2016

Biochemical Society Transactions

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Receptor activity-modifying proteins (RAMPs) are single pass membrane proteins initially identified by their ability to determine the pharmacology of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR). It is now known that RAMPs can interact with a much wider range of GPCRs. This review considers recent developments on the structure of the complexes formed between the extracellular domains (ECDs) of CLR and RAMP1 or RAMP2 as these provide insights as to how the RAMPs direct ligand binding. The range of RAMP interactions is also considered; RAMPs can interact with numerous family B GPCRs as well as examples of family A and family C GPCRs. They influence receptor expression at the cell surface, trafficking, ligand binding and G protein coupling. The GPCR-RAMP interface offers opportunities for drug targeting, illustrated by examples of drugs developed for migraine.

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Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

Cited by 64 publications

References 51 publications

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

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